There exists a large group of acute and chronic neuropsychiatric disorders for which safe and clinically effective treatments are not currently available. This diverse group of disorders encompasses a broad spectrum of initial events which are characterised by the initiation of progressive processes that sooner or later lead to neuronal cell death and dysfunction. Stroke, cerebral ischaemia, trauma or a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease are all commonly occurring conditions that are associated with neurodegeneration of the brain and/or spinal cord.
The ongoing search for potential treatments of neurodegenerative disorders has involved investigation of excitatory amino acid antagonists, inhibitors of lipid peroxidation, calcium channel antagonists, inhibitors of specific pathways of the arachidonic acid cascade, kappa opioid agonists, adenosine agonists, PAF antagonists and diverse other agents. At the present time there is no consensus of the relative importance of the role played by compounds belonging to any of these general classes.
In a paper on the reactions of 2-halothiazoles with ketone enolates, J. F. Wolfe and co-workers (J. Org. Chem., 1986, 51, 1184-1188) describe bis(2-thiazolyl) derivatives of the following formula: ##STR3##
In a paper on the synthesis of 2-aroyloxazoles (Synthesis, 1984, 1048-1050), the following compound is disclosed: ##STR4##
No pharmacological activity is associated with any of the above compounds. The substitution pattern of the above compounds places them outside the scope of the present invention.
In patent application DE 2801794 (US 4371734) a process for the preparation of thiazoles of general formula: ##STR5## is claimed. A specific example of said thiazoles is 4-methyl-.alpha.-(4-phenyl-2-thiazolyl)-2-thiazoleacetonitrile. Said compounds are useful as intermediates in the preparation of certain dyestuffs. No pharmacological action is ascribed to said compounds. The definition of the groups R.sub.1 and R.sub.2 places these compounds outside the scope of the present invention.
In a paper on the synthesis of deuterium--labelled thiazoles, Roussel and Metzger (Bull. Soc. Chim. Fr., 1962, 2075-2078) describe the isolation and partial characterisation of 1,1-di(2-thiazolyl)ethanol. No pharmacological activity is associated with this compound. This compound is deleted from the scope of the present invention by a disclaimer in claim 1.
The present invention
A primary objective of the present invention is to provide structurally novel heterocyclic compounds which by virtue of their pharmacological profile are expected to be of value in the treatment of acute and chronic neuropsychiatric disorders characterised by progressive processes that sooner or later lead to neuronal cell death and dysfunction. Such disorders include stroke; cerebral ischaemia; dysfunctions resulting from brain and/or spinal trauma; hypoxia and anoxia, such as from drowning, and including perinatal and neonatal hypoxic asphyxial brain damage; multi-infarct dementia; AIDS dementia; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, epilepsy, multiple sclerosis and amytrophic lateral sclerosis; brain dysfunction in connection with surgery involving extracorporeal circulation or in connection with brain surgery, including endarterectomy of the carotid arteries; and CNS dysfunctions as a result of exposure to neurotoxins or radiation. This utility is manifested, for example, by the ability of these compounds to inhibit delayed neuronal death in the gerbil bilateral occlusion model of ischaemia.
The present invention relates to a compound having the general formula (1) ##STR6## wherein: X.sub.1 and X.sub.2 are independently O, S or Se;
Y.sub.1 and Y.sub.2 are independently C or N with the proviso that at least one of Y.sub.1 and Y.sub.2 is N; PA1 Y.sub.3 and Y.sub.4 are independently C or N with the proviso that at least one of Y.sub.3 and Y.sub.4 is N; PA1 R.sub.1 and R.sub.2 each represent one or more groups independently selected from H, lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, lower acyloxy-lower alkyl or CF.sub.3 ; PA1 and A is ##STR7## wherein W is O, S, NH or N-lower alkyl, PA1 geometrical and optical isomers and racemates thereof where such isomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof; PA1 W is O, NH or N-lower alkyl; PA1 and R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as previously defined above. PA1 1,1-bis(4,5-dimethyl-2-thiazolyl)ethanol; PA1 1,1-di(2-thiazolyl)-2,2,2-trifluoroethanol; PA1 and pharmaceutically acceptable acid addition salts or solvates thereof. PA1 or (d), particularly in cases where R.sub.4 is perfluoroalkyl, reacting a compound of general formula (8) with a silyl derivative of general formula R.sub.4 SiMe.sub.3. PA1 R.sub.7 is perfluoroalkyl or ##STR19## and X.sub.1 and X.sub.2 are independently O, S or Se; with the proviso that di(2-thiazolyl) ketone is excluded. PA1 (i) direct separation by means of chiral chromatography, for example, by HPLC using a chiral column; PA1 or (ii) recrystallisation of the diastereomeric salts formed by reacting the base (1) with an optically active acid; PA1 or (iii) derivatization of the compound of formula (1) by reaction with an optically active reagent, separation of the resultant diastereoisomeric derivatives by, for example, crystallisation or chromatography, followed by regeneration of the compound of formula (1).
R.sub.3 is H, lower alkyl or lower acyl, or WR.sub.3 is H, PA2 R.sub.4 is lower alkyl or lower perfluoroalkyl, or R.sub.3 and R.sub.4 together form a ring ##STR8## wherein n is 2, 3 or 4, R.sub.5 and R.sub.6 independently are H or lower alkyl;
with the proviso that 1,1-di(2-thiazolyl)ethanol is excluded.
The expression "pharmaceutically acceptable acid addition salts" is intended to include but is not limited to such salts as the hydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulphate, dihydrogen phosphate, ethanedisulphonate, mesylate, fumarate, maleate and succinate.
Preferred embodiments of this invention relate to compounds having the general formula (2) ##STR9## wherein: X.sub.1 and X.sub.2 are independently O or S; and W, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as previously defined above.
More preferred embodiments of this invention relate to compounds having the general formula (3) ##STR10## wherein: X.sub.1 and X.sub.2 are independently O or S;
Analogous compounds wherein X.sub.1 and/or X.sub.2 are Se, for example, 1,1-bis(2-selenazolyl)-2,2,2-trifluoroethanol and 1,1-bis(2-selenazolyl)ethylamine are specifically included within the scope of the invention.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all geometrical and optical isomers and racemates thereof where such isomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof such as for instance hydrates.
The following definitions shall apply throughout the specification and the appended claims.
Unless otherwise stated or indicated, the term "lower alkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and straight- and branched-chain pentyl and hexyl.
Unless otherwise stated or indicated, the term "lower perfluoroalkyl" denotes a straight or branched alkyl group having from 1 to 4 carbon atoms fully substituted by fluorine. Examples of said lower perfluoroalkyl groups include trifluoromethyl, pentafluoroethyl and heptafluoroisopropyl.
Unless otherwise stated or indicated, the term "lower acyl" denotes a straight or branched acyl group having from 1 to 6 carbon atoms. Examples of said lower acyl include formyl, acetyl, propionyl, iso-butyryl, valeryl, and pivaloyl.
Unless otherwise stated or indicated, the term "hydroxy-lower alkyl" denotes a lower alkyl group as defined above substituted by a hydroxy group. Examples of said hydroxy-lower alkyl include hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.
Unless otherwise stated or indicated, the term "lower acyloxy-lower alkyl" denotes a lower alkyl group as defined above substituted by an oxygen atom which itself bears a lower acyl group as defined above. Examples of said lower acyloxy-lower alkyl include acetoxymethyl, propionyloxymethyl, 1-acetoxyethyl and 2-acetoxyethyl.
Unless otherwise stated or indicated, the term "lower alkoxy" denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
Unless otherwise stated or indicated, the term "lower alkoxy-lower alkyl" denotes a lower alkyl group as defined above substituted by a lower alkoxy group as defined above. Examples of said lower alkoxy-lower alkyl include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl.
Among the most preferred compounds of formula (1) according to the present invention are:
The present invention also relates to processes for preparing the compound having formula (1). Throughout the following general description of such processes it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups are described, for example, in "Protective Groups in Organic Synthesis", T. W. Greene, Wiley-Interscience, New York, 1981.
Said compound wherein A is ##STR11## may be prepared by (a) reacting a compound of general formula (4) with an organometallic derivative of general formula (5) ##STR12## or (b) reacting a compound of general formula (6) with an organometallic derivative of general formula (7) ##STR13## or (c) reacting a compound of general formula (8) with an organometallic derivative of general formula R.sub.4 M ##STR14## and quenching the reaction mixture with a proton source (R.sub.3 is H) or an alkylating (R.sub.3 is lower alkyl) or acylating (R.sub.3 is lower acyl) reagent,
Alternatively, the compound of formula (1) wherein A is ##STR15## may be first obtained as above and then converted into the compound wherein R.sub.3 is lower alkyl or lower acyl.
The processes (a), (b) or (c) can be achieved for example, by reacting together a ketone of structure (4) or (6) or (8) with a preformed organometallic derivative (5) or (7) or R.sub.4 M respectively in a suitable anhydrous solvent such as diethylether, tetrahydrofuran or hexane or mixtures thereof. Said reaction should be conducted at a suitable temperature, normally between -100.degree. C. and +50.degree. C. and preferably under an inert atmosphere, normally nitrogen or argon. In a specific variation, a solution of the ketone of structure (4) or (6) or (8) in anhydrous diethylether or tetrahydrofuran is added dropwise to the organometallic derivative (5) or (7) or R.sub.4 M respectively in anhydrous diethylether or tetrahydrofuran or hexane or mixtures thereof at a temperature of about -50.degree. C. to -78.degree. C. and under an atmosphere of nitrogen. After a suitable period of time the reaction mixture is allowed to warm to room temperature and then quenched by the addition of water or a lower alcohol. The required product (1) wherein A is ##STR16## may then be isolated and purified and characterised using standard techniques.
The process (d) can be achieved, for example, by treating a solution of the ketone (8) and the silyl derivative R.sub.4 SiMe.sub.3 in a suitable anhydrous solvent such as diethylether or tetrahydrofuran with tetrabutylammonium fluoride. Said reaction should be conducted at a suitable temperature, normally between -100.degree. C. and +50.degree. C. and preferably under an inert atmosphere, normally nitrogen or argon. After a suitable period of time the reaction mixture is allowed to come to room temperature and is then treated with 6M hydrochloric acid. The required product (1) wherein A is ##STR17## may then be isolated and purified and characterised using standard techniques.
Ketones of general formula (4) or (6) or (8) are either compounds which are commercially available or have been previously described in the literature, or compounds which can be prepared by the straightforward application of known methods.
Thus, the present invention also refers to some new intermediates of general formula (9), namely: ##STR18## wherein: R.sub.1 and R.sub.2 are as defined above;
In the organometallic derivatives of general formula (5) or (7) or R.sub.4 M, M represents a metallic residue such as Li or Mg-halogen. Such compounds are either commercially available or have been previously described in the literature, or can be prepared by the straightforward application of known methods of organometallic chemistry.
Silyl derivatives of formula R.sub.4 SiMe.sub.3 are either commercially available, for example, CF.sub.3 SiMe.sub.3, or have been previously described in the literature or can be prepared by the straightforward application of known methods.
Compounds of formula (1) wherein A is ##STR20## may be prepared by
(a) elimination of HWR.sub.3 from a compound of formula (1) wherein A is ##STR21## or (b) by using a compound of general formula (8) as the substrate for a standard alkene forming reaction such as the Wittig reaction, the Peterson reaction or the McMurry reaction.
The process (a) can be achieved, for example, by treatment of a solution of a compound of formula (1) wherein A is ##STR22## in a suitable inert solvent with an acid or a base or a reagent such as thionyl chloride or phosphorus oxychloride. Said reaction should be conducted at a suitable temperature, normally between -20.degree. C. and the reflux temperature of the solvent. In a preferred variation, a solution of a compound of formula (1) wherein A is ##STR23## in a solvent such as dichloromethane or chloroform at 0.degree. C. to 10.degree. C. is treated with an acid such as anhydrous hydrogen chloride or p-toluenesulphonic acid, or with thionyl chloride. The reaction is then allowed to proceed at ambient temperature or above. The required product (1) wherein A is ##STR24## may then be isolated and purified and characterised using standard techniques.
Compounds of formula (1) wherein A is ##STR25## may be prepared by (a) using a compound of general formula (1) wherein A is ##STR26## as the substrate for a Ritter reaction, or (b) by using a compound of general formula (1) wherein A is ##STR27## as the substrate for a Mitsunobu-type reaction, or (c) reacting a compound of general formula (1) wherein A is ##STR28## with trimethylsilylazide, Me.sub.3 SiN.sub.3, in the presence of a Lewis acid such as boron trifluoride diethyletherate to give an azide of formula (1) wherein A is ##STR29## and then reducing said azide using, for example, hydrogen in the presence of a palladium or platinium catalyst.
Some compounds of general formula (1) contain an asymmetric centre and can thus exist in enantiomeric forms. These enantiomers may be separated using methods that will be well known to one skilled in the art. Such methods include, for example,
Alternatively, compounds of formula (1) may be obtained directly in an optically active form by using a chemical or enzymatic based method of asymmetric synthesis.
Some compounds of general formula (1) wherein A is ##STR30## can exist as E and Z (trans and cis) isomers. Such isomers may be separated using standard techniques, for example, crystallisation or chromatography, that will be readily apparent to one skilled in the art.
Pharmacology
The neuroprotective properties of the compounds of formula (1) are exemplified by their ability to inhibit delayed neuronal death in the gerbil bilateral occlusion model of ischaemia.
Animals used were male Mongolian gerbils (60-80 g). Drugs were dissolved in isotonic saline containing dimethylsulphoxide.
Ischaemia was induced in the gerbils by 5 minute occlusion of both carotid arteries following the procedure described by R. Gill, A. C. Foster and G. N. Woodruff, J. Neuroscience. 1987, 7, 3343-3349. Body temperature was maintained at 37.degree. C. throughout. Restoration of blood flow after occlusion was checked visually and the animals were allowed to survive for 4 days. The extent of neuronal degeneration in the hippocampus was then assessed. The test compounds were administered (i.p.) as a single dose 60 minutes following occlusion. No administration was made prior to the occlusion. The effectiveness of the compounds of formula (1) in decreasing damage to the CA1/CA2 hippocampal neurones in gerbils following ischaemic insult clearly illustrates the usefulness of these compounds in preventing neurodegeneration. These compounds are therefore expected to be of value in the treatment of acute and chronic neuropsychiatric disorders characterised by progressive processes that sooner or later lead to neuronal cell death and dysfunction.
Pharmaceutical Formulations
The administration in the novel method of treatment of this invention may conveniently be oral, rectal, topical or parenteral at a dosage level of, for example, about 0.01 to 1000 mg/kg, preferably about 1.0 to 500 mg/kg and especially about 5.0 to 200 mg/kg and may be administered on a regimen of 1 to 4 doses or treatments per day. The dose will depend on the route of administration, preferred routes being oral or intravenous administration. It will be appreciated that the severity of the disease, the age of the patient and other factors normally considered by the attending physician will influence the individual regimen and dosage most appropriate for a particular patient.
The pharmaceutical formulations comprising the compound of this invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral solutions or suspensions for parenteral administration; suppositories for rectal administration; or suitable topical formulations. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals--The Science of Dosage Form Design", M. E. Aulton, Churchill Livingstone, 1988.
To produce pharmaceutical formulations containing a compound according to the present invention in the form of dosage units for oral application the active substance may be admixed with an adjuvant/a carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds.
For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the active substance using either the above mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.
Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.02% to about 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to the man in the art.
Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may involve the use of surface acting agents to improve solubility. They may conveniently be provided in various dosage unit ampoules.
Except where otherwise indicated, the necessary starting materials for all Preparations and Examples were purchased commercially.